Cancer is a leading cause of death worldwide. Despite significant advances in the field of chemotherapy, many of the most prevalent forms of cancer still resist chemotherapeutic intervention. Over the past several years, antisense oligodeoxynucleotides (ODNs) have been proposed as therapeutic molecules for the treatment of cancer. Several antisense ODNs targeting a variety of molecules have been shown to have antiproliferative effects against neoplastic cells in vitro and in vivo (Gewirtz, 2000, J. Clin. Oncol. 18:1809-1811), and several have demonstrated anti-tumor activity and limited toxicity in Phase I clinical trials (Smith and Wickstrom, 2000, Methods Enzymol. 314:537-580). However, use of antisense ODNs for inhibition of gene expression raises several problems, including possible degradation by nucleolytic enzymes and the difficulty antisense ODNs have in crossing biological membranes and entering cells.
The c-myc protein is a member of the helix-loop-helix/leucine zipper (HLH/LZ)1 family of transcription factors that forms heterodimers with Max (Ayer & Eisenman, Genes Devel. 7:2110-2119, 1993). In general, trans-activating Myc:Max heterodimers are found in proliferating cells, while trans-repressing Mad:Max heterodimers are found in differentiated cells. C-myc protein level influences cell proliferation, differentiation, and neoplastic transformation, presumably by affecting the balance between Myc:Max and Mad:Max heterodimers (Spencer & Groudine, Adv. Cancer. Res. 56:1-48, 1991).
When c-myc protein is overexpressed or is induced at inappropriate times, this balance is perturbed, and cell proliferation and differentiation are disrupted. For example, c-myc overexpression prevents or delays cell differentiation (Coppola & Cole, Nature 320:760-763, 1986). It also blocks serum-starved cells from entering the Ga phase of the cell cycle and instead induces them to undergo apoptosis. Overexpression of c-myc has also been implicated in tumor formation in experimental animals and in human patients with Burkitt's lymphoma (Klein, Genes, Chromosomes, Cancer 1:3-8, 1989). These and other deleterious consequences of aberrant c-myc expression highlight the importance of proper c-myc gene regulation and how unregulated expression of this gene can result in cell proliferative disorders.
Given the specificity of antisense ODNs toward their mRNA targets and the role played by c-myc overexpression in cancer, what is needed, therefore, is an antisense ODN therapeutic capable of decreasing or eliminating c-myc protein expression in proliferating cells expressing c-myc mRNA and protein.
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